Interleukin-1 Biology
Interleukin-1 (IL-1) is a potent pro-inflammatory cytokine that can be produced by a variety of cell types, including mononuclear phagocytes, in response to infection and inflammation. The IL-1 family consists of two agonists, IL-1α and IL-1β and a naturally occurring receptor antagonist, the IL-1 receptor antagonist (IL-1Ra) (Dinarello, C A, Blood 1996, 87(6): 2095-147). Two IL-1 receptors, IL-1R type I and IL-1R type II, have been identified. Both receptors can interact with all three forms of the IL-1 family molecules. IL-1RI is responsible for mediating IL-1-induced cellular activation. However, the IL-1/IL-1RI complex cannot signal by itself, but is dependent on association with a second receptor chain, IL-1R Accessory Protein (IL-1RAcP) (Dinarello, C A, Blood 1996, 87(6): 2095-147). In contrast to IL-1RI, IL-1RII does not induce cellular activation upon binding to IL-1 and thus IL-1RII functions as regulatory decoy receptor, leading to a net decrease in IL-1 available to bind to IL-1RI.
IL-1Ra is structurally related to IL-1 and is capable of binding to IL-1RI but fails to interact with IL-1RAcP and is thus incapable of inducing cellular activation (Dinarello, C A, Blood 1996, 87(6): 2095-147, Arend, W. P. and C. Gabay, Arthritis Res 2000 2(4): 245-8). Thus, IL-1Ra inhibits the pro-inflammatory effects of IL-1 by functioning as a competitive inhibitor in receptor binding. IL-1Ra has also been shown to bind to IL-1RII but with a lower affinity compared to IL-1.
IL-1 is a potent pro-inflammatory cytokine, which is induced at sites of local infection or inflammation and is involved in the regulation of a variety of physiological and cellular events (summarised in Dinarello C A, CHEST, 2000, 118: 503-508 and Dinarello, C A, Clin Exp Rheumatol, 2002, 20(5 Suppl 27): S1-13). It is capable of activating several cell types including leukocytes and endothelial cells. IL-1 induces and amplifies immunological responses by promoting the production and expression of adhesion molecules, cytokines, chemokines and other inflammatory mediators such as prostaglandin E2 and nitric oxide (NO). As a consequence, local inflammation is amplified and sustained. In addition, the IL-1-induced production of inflammatory mediators results in fever, headache, hypotension and weight loss. Furthermore, IL-1 is a hematopoietic growth factor and has been shown to reduce the nadir of leukocytes and platelets in patients during bone marrow transplantation. IL-1 has also been shown to promote angiogenesis by inducing the production of vascular endothelial growth factor, thereby promoting pannus formation and blood supply in rheumatic joints. Finally, IL-1 has been shown to promote the bone and cartilage degradation in rheumatic diseases.
Role of IL-1 in Disease
Given the vast array of effects on several tissues mediated by IL-1, including its important role as an inflammatory mediator and capability of promoting angiogenesis, IL-1 has been implicated in the pathogenesis of several autoimmune and auto-inflammatory diseases as well as in other disease conditions. Thus, the effect of prevention of the IL-1-IL-1R interaction has been investigated in several indications. In rheumatoid arthritis (RA), treatment with IL-1Ra has been shown to reduce disease severity in several studies (Bresnihan, B., et al., Arthritis Rheum, 1998 41(12): 2196-204, Nuki, G., et al., Arthritis Rheum, 2002. 46(11): 2838-46, Cohen, S., et al., Arthritis Rheum, 2002 46(3): 614-24, Cohen, S. B., et al., Ann Rheum Dis, 2004 63(9):1062-8). Although wild type IL-1Ra was capable of reducing the signs and symptoms of disease, it was less effective than e.g. blockade of the tumour necrosis factor (TNF) pathway in ameliorating disease. The poor efficacy of IL-1Ra in controlling disease severity in RA could potentially be due to an insufficient receptor affinity or plasma half-life of IL-1Ra (Burger D et al., Best Pract Res Clin Rheumatol. 2006 20(5):879-96).
In addition to RA, IL-1R blockade using IL-1Ra has been shown to effectively reduce disease severity in a number of disease conditions. In several indications IL-1Ra treatment rapidly induced complete or near-complete remissions and thus was more effective in amelioration of disease symptoms than in RA. IL-1Ra treatment in systemic onset juvenile idiopathic arthritis (SOJIA) clearly demonstrated that IL-1 plays an important role in pathogenesis (Pascual V et al., J Exp Med, 2005 201(9): 1479-1486). A complete remission was obtained in seven out of nine patients refractory to other therapies and a partial response was seen in the remaining two patients.
In addition, IL-1Ra treatment has shown dramatic effects in amelioration of disease in several auto-inflammatory conditions associated with dysregulated IL-1 production. Familial cold auto-inflammatory syndrome (FCAS), Muckle-Wells disease and neonatal onset multi-system inflammatory disease (NOMID) are all caused by mutations in the CIAS1/NALP3/cryopyrin gene. These mutations result in the over-activation of the inflammasome, resulting in an over-production of IL-1 (Burger D et al., Best Pract Res Clin Rheumatol. 2006 20(5):879-96). Treatment of patients with IL-1Ra resulted in a dramatic reduction in disease symptoms. Small studies and case reports published for all three diseases demonstrated rapid and complete or near-complete remissions (Hawkins P et al., Arthritis Rheum. 2004 50(2):607-12, Hawkins P et al., N Engl J Med. 2003 Jun. 19; 348(25):2583-4, Boschan et al, Am J Med Genet A, 2006 Apr. 15; 140(8):883-6, Lovell D J, Arthritis Rheum, 2005 April; 52(4):1283-6 and Hoffman H et al., Lancet. 2004 364(9447):1779-85) clearly demonstrating that IL-1 plays an important role in pathogenesis and that IL-1Ra effectively prevents disease.
Similar to diseases caused by mutations in CIAS1/NALP3/cryopyrin, mutations in the pyrin gene, negatively regulating the inflammasome, also result in dysregulated IL-1 production. Mutations in pyrin are associated with the periodic fever syndrome familial Mediterranean fever (FMF) as well as with pyogenic arthritis pyoderma gangrenosum and acne (PAPA) syndrome. Treatment of a FMF patient resulted in reduction in the systemic inflammatory response (Chae J J et al., Proc Natl Acad Sci USA. 2006 103(26):9982-7). Similarly, a case of IL-1Ra treatment upon knee inflammation flares in a PAPA patient demonstrated rapid and complete resolution of inflammation (Dierselhuis M P et al., Rheumatology (Oxford). 2005 44(3):406-8).
Examples of other auto-inflammatory diseases in which IL-1ra treatment has been shown to dramatically reduce disease severity include adult onset Still's disease (Ruiz P J et al., Ann Rheum Dis. 2007 6(3):422-3, Rudinskaya A, J Clin Rheumatol. 2003 9(5):330-2, Vasques Godinho F M et al. Ann Rheum Dis. 2005 64(4):647-8, Fitzgerald A A et al., Arthritis Rheum. 2005 52(6):1794-803) and hyper-IgD syndrome (Bodar E J et al., Neth J Med. 2005 July-August; 63(7):260-4). IL-1 has also been implicated in the pathogenesis of osteoarthritis, and is known to induce proteases involved in cartilage destruction as well as sustaining local inflammation and cartilage erosion. The effect of IL-1Ra treatment was investigated in a small clinical study and demonstrated a beneficial effect in treated patients (Chevalier X, J Rheumatol, 2005 32:1317-23).
Finally, the effect of IL-1ra treatment has been investigated in type 2 diabetes mellitus. The rationale behind this is that IL-1Ra production is reduced in pancreatic islets of type 2 diabetes patients. In addition, high glucose has been shown to induce production of IL-1 in pancreatic beta cells, leading to impaired insulin secretion, decreased proliferation and apoptosis. In a clinical trial of 34 IL-1Ra-treated patients and 35 placebo patients, IL-1Ra was shown to improve glycemia and beta cell secretory function as well as to reduce markers of systemic inflammation (Larsen C M et al. N Engl J Med. 2007 Apr. 12; 356(15):1517-26).
Importantly, although wild type IL-1Ra treatment has been shown to effectively ameliorate disease, daily injections are required for optimal clinical effects. In addition, withdrawal of treatment results in a rapid disease flare in several indications (Burger D et al., Best Pract Res Clin Rheumatol. 2006 20(5):879-96) supporting the notion that the clinical usefulness of wild type IL-1Ra is limited by its short half-life. Thus, an IL-1Ra variant with improved functional activity or enhanced in vivo half-life, resulting in more sustained clinical effect would facilitate less frequent injections or improve pharmaceutical efficacy.
Hence, the present invention seeks to provide improved therapeutic agents for the treatment of diseases associated with interleukin-1 receptor function.